Lyme borreliosis A69.2

Lyme disease" includes all clinical manifestations of human beings caused by infections with B. burgdorferi s.l. (see below Borrelia bacteria) according to the definition made in 1985 in Vienna at the "Second International Symposium on Lyme Disease and Related Disorders". According to this, Lyme disease in humans is a multisystemic spirochetosis, which can progress both as a mild local infection and as a stadium-like chronic multisystemic spirochetosis. Lyme borreliosis is the most common tick-borne infectious disease. The causative agent is transmitted by ticks(Ixodes ricinus, the common wood tick).

Borrelia burgdorferi (see below Borrelia): filamentous, coiled, vividly mobile spirochete. Carriers are ticks (Ixodes ricinus, I. dammini and others), which are ubiquitous in Central, Eastern and Northern Europe and America, rarely also insects, e.g. Stomoxys calcitrans.

About 5-35% of ticks are infected with Borrelia, with adult ticks infected to about 20%, nymphs to 10% and larvae to about 1%. Diaplacental infection is possible.

In Europe, 5 pathogenic species of B. burgdorferi have been described so far:

• B. afzelii
• B. garinii
• B. bavariensis
• B. burgdorferi sensu stricto
• B. spielmanii

Borrelia burgdorferi sensu lato is transmitted by tick bites in Europe. In the USA, only B. burgdorferi sensu stricto is observed.

Most common tick-borne disease in Europe and North America. About 5-35% of ticks are infected with Borrelia. In Europe all 3 groups of Borrelia are present. Furthermore on the west and east coast of the USA. Borrelia infections also occur in China.

Incidence: There are only rough estimates on the incidence of Lyme borreliosis in humans in Germany, since so far only some federal states (Berlin, Brandenburg, Mecklenburg-Western Pomerania, Rhineland-Palatinate, Saarland, Saxony, Saxony-Anhalt, Thuringia) have mandatory reporting requirements. Notifiable manifestations of Lyme disease are erythema migrans, early neuroborreliosis and acute Lyme arthritis.

In 2009, the annual incidence in the former East Germany was 34.7 reported cases per 100,000 inhabitants. Results of two population-based prospective cohort studies in southern Germany showed annual incidences between 111 and 260 cases per 100,000 inhabitants. The number of new cases per year in Germany is estimated to be between 50,000 and 100,000.

Adult ticks are infested to an average of 20%, nymphs to 10% and larvae to only about 1%. After a tick bite, an infection (seroconversion) can be expected in 1.5-6% of those affected and a manifest disease in 0.3-1.5%. The risk of infection is greatest from the end of May to the end of July; infections are rarer in autumn or on warm winter days.

All age groups are affected.

Classification into 3 stages, whereby each stage can represent the initial manifestation of the disease and stages can be skipped (see Table 1):

• Stage I (localized early infection): The leading symptom is erythema chronicum migrans. It may be accompanied by regional swelling of the lymph nodes and mild general symptoms (fever, fatigue, headache). In this stage of the disease, the borrelia serology is usually negative. The clinical findings are diagnostic.
• Stage II (disseminated early infection; 6-8 weeks after the tick bite.) Often no clinical symptoms):
  • Nonspecific exanthema, cheek erythema, erythema nodosum, arthralgias, myalgias, myo-/pericarditis, recurrent hepatitis, conjunctivitis, possibly panophthalmitis, swelling of lymph nodes and spleen. Under certain circumstances severe feeling of illness.
  • Lymphadenosis cutis benigna (lymphocytoma)
  • Early neuroborreliosis: meningopolyneuritis Garin-Bujadoux-Bannwarth (severe nocturnal headache, unilateral radiculitis with painful paralysis, possibly discrete encephalitis).
  • The (rare) multiple occurrence of the clinically classic "erythema chronicum migrans" is to be seen as a cutaneous sign of dissemination of the Borrelia infection. More frequent in the context of disseminated early infection are large, homogeneous bright red, sharply demarcated, little symptomatic circular or oval erythemas; not infrequently they are also only discreetly perceptible or only visible in the presence of heat. In children, the face is usually also affected (differential diagnosis!).
• Stage III (late infection with organ manifestation): In Europe, neurological symptoms in the form of a Bannwarth syndrome occur in this stage. Bannwarth syndrome describes severe radicular pain, especially at night, with asymmetric paresis of the extremities. In addition, cranial nerve deficits may occur (frequently facial nerve paresis (1/3 of cases on both sides) and abducens paresis). In the USA, Lyme arthritis is observed more frequently. Stage III is always accompanied by a positive Borrelia serology. A negative serological result excludes the disease!
  • The leading clinical-dermatological symptom of stage III in Europe is acrodermatitis chronica atrophicans (for clinic and differential diagnosis, see there).
  • Rarely, nodular panniculitis is observed as a hyperergic reaction to a Borrelia infection....
  • Lyme arthritis is characterized by a typical joint pattern with mono- or oligoarthritis.
  • A double infection with the early summer meningoencephalitis virus is very rare. Clinical sign is the picture of "progressive encephalomyelitis", similar to encephalomyelitis disseminata (multiple sclerosis).

Post-infectious Lyme disease syndrome: Even after healing of the borrelia-typical HV through sufficient antibiotic therapy, a general feeling of illness with muscle and joint pain can persist for months.

Reminder. Lyme borreliosis does not have to pass through every stage, but can skip a stage or only become clinically manifest with stage II or III!

Antibodies can be detected in the first 2 weeks after infection in 50% of patients, and after > 4 weeks in 80% of patients. Serological parameters cannot distinguish between an active and a past infection (antibodies remain for months to years even after adequately treated infection).

The guidelines of the microbiological quality standards (MiQ = acronym for "Quality standards in microbiological-infectiological diagnostics") recommend the detection of separate IgG and IgM antibodies with a sensitive ELISA and, in case of positivity, an analysis with a specific immunoblot.

Due to the diagnostic gap of 2-5 weeks for IgM and 2-3 months for IgG, Borrelia antigens can be detected by PCR from infected skin material.

Experimental: Attempt to culture the pathogen from bioptic material (Barbour-Stoenner-Kelly medium in a microaerophilic environment at a temperature of 33 °C).

The interpretation of the findings is made against the background that the antibody prevalence of the normal population is about 1% in young children and >25% in persons >60 years.

Neuroborreliosis: For the detection of neuroborreliosis, the determination of the CSF serum index has a high diagnostic value. This determines whether antibodies (intrathecally formed AK) against Borrelia are produced in the CSF. In connection with a lymphocytic pleocytosis (as a rule, the leucocyte count is < 1000/ul, in the case of clear lymphocytosis), protein elevation (1 g/l and more) and barrier disturbance, the diagnosis can be confirmed in most cases. Sometimes AK are already found when the serum antibody test is still negative or still in the borderline range.

Early infection:

• Erythema chronicum migrans (DD: see there):
• Lymphadenosis cutis benigna (DD: see there)

Disseminated early infection:

• Erythema anulare centrifugum. Multiple, partly anular, partly polycyclic, slowly centrifugally growing plaques, typically smooth on the surface, with little or no pruritus. Almost pathognomonic is the palpatory finding (resembling a wet woollen thread): with a rough marginal ridge. Histology is often characteristic. Positive serology is expected in this phase of Lyme disease.
• Medicinal exanthema, maculo-papular: Serological evidence of Borrelia infection can always be obtained in this phase of infection.
• If facial erythema occurs in children: Erythema infectiosum: Acute clinical picture with butterfly-shaped redness and swelling of the cheeks (in 75% of sufferers: slapped cheeck appearance).

Late infection of the skin

• Acrodermatitis chronica atrophicans (DD: see there)
• Atrophodermia idiopathica et progressiva

Development of cutaneous B-cell lymphomas has been described in isolated cases (see: Primary cutaneous marginal zone lymphoma).

Stage I:

• In localized early infection (erythema chronicum migrans) oral doxycycline therapy (2x100mg/day p.o. or 200mg 1x/day p.o.) for 14 days. A higher dosage is not necessary.
• Alternative: Amoxicillin (e.g. Amoxicillin ratiopharm) 3 times/day 500 (-750) mg p.o. for 14 days.
• Alternative: Cefuroxime (e.g. Cefuhexal) 2 times/day 500 mg p.o. for 14 days.
• Alternative: Azithromycin 2x250mg p.o. for 10 days.
• Children:
  • Amoxicillin 50 mg/kg bw/day p.o. divided into 3 daily doses over 14 days.
  • Alternative: Cefuroxime (e.g. Cefuhexal) 20-30 mg/kg bw p.o. divided into 2 daily doses over 14 days.
  • From 9 years of age, doxycycline (e.g. Doxycycline AL) 100 mg p.o. 2 times/day or 4 mg/kg bw/day for 14 days. In children <8 years of age doxycycline is contraindicated.

Stage II:

• Doxycycline 1 time/day 200 mg p.o. for 21 days.
• Alternative: Amoxicillin 3 times/day 750 mg p.o. for 21 days
• Alternative: Cefuroxime 2x500mg for 21 days
• Alternative: Ceftriaxone (e.g. Rocephin, Ceftriaxon® ratiopharm) 1 time/day 2 g i.v. for 21 days.
• Mild stage II manifestations should be treated orally for 2 weeks, this also applies to children.
• Infestation of the central nervous system:
  • In this constellation, systemic application of cephalosporins such as ceftriaxone, e.g. Rocephin® 1 time/day 2 g i.v. for 21 days, should be preferred in all cases. The antibiotic cycles should be repeated at 3-monthly intervals, depending on the clinic, and should last at least 14 days due to the generation times of the Borrelia.
    • Children:
      • Ceftriaxone (e.g. Rocephin, Ceftriaxon ratiopharm) 50-100 mg/kg bw/day i.v. for 14 days.
      • Alternatively: Cefotaxim 200 mg/kg bw/day, max. 3 times/day 2 g i.v. for 14 days (see above regarding therapy repetitions). Benzylpenicillin 500,000 IU/kg bw/day, max. 10 million IU/day, 4-6 ED i.v. for days.
      • From age > 9 years: Doxycycline (e.g. Doxycycline AL) 2 times/day 100 mg p.o. or 4 mg/kg bw/day for 14 days.

Stage III: The duration of a therapy cycle should be 3 to a maximum of 4 weeks. Acrodermatitis chronica atrophicans and Borrelia arthritis can be treated primarily with an oral antibiotic.

• Doxycycline 1 time/day 200 mg p.o. for 21 days.
• Alternative: Amoxicillin 3 times/day 750 mg p.o. for 21 days.
• Alternative: In case of insufficient clinical response, recurrence or complete treatment failure, therapy should be switched to i.v. treatment, e.g. ceftriaxone 1 time/day 2 g i.v. (alternative: cefotaxime 3 times/day 2 g i.v.) for 21 days or penicillin G 4 times/day 5 mega i.v. for 21 days.
• Borrelia carditis: Analogous to clinical stage II.
• Borrelia arthritis: Analogous to clinical stage II.

• Notice. Acrodermatitis chronica atrophicans: The activity of the process should be controlled clinically and histologically! Antibody titer controls are not very informative for the course of the healing process, therefore it is better to use a Borrelia PCR for this purpose. Skin atrophies are only reversible to a small extent.

  • In children and in pregnancy:
    • Amoxicillin (e.g. Amoxicillin ratiopharm®) 50 mg/kg bw/day p.o. in 3 doses.
    • Alternative: Ceftriaxone (e.g. Rocephin®) 20-80 mg/kg bw/day i.v.
    • Alternative: Erythromycin (e.g. Erythro-Hefa® juice) 3 times/day 100-500 mg p.o.
    • Alternative: Clarithromycin (e.g. Klacid®) 15 mg/day/kg bw for 7-10 days.

In immunocompromised patients: Therapy recommendations at each stage remain unchanged. Pregnancy:

• In erythema chronicum migrans: amoxicillin (3 times/day 500 mg p.o. for 2-3 weeks), in case of strict indication cefuroxime 2 times/day 500 mg p.o. for 2-3 weeks); in case of beta-lactam allergy azithromycin (2 times/day 250 mg p.o. for 2-5 days) is recommended. Penicillin V is also an alternative.

Post-infectious Lyme disease syndrome (post Lyme disease):

• These postinfectious "rheumatoid" symptoms are treated consistently with antiphlogistic therapy.

Cheap. Most symptoms are self-limiting. Different course of the disease in Europe and North America. Spontaneous healing in stage 1 (erythema chronicum migrans as sole symptom) is much more frequent in Europe than in the USA, where organ involvement is more prevalent. Typical manifestation of stage 3 of the disease is acrodermatitis chronica atrophicans in Europe and lyme arthritis in North America.

Even after the healing of the skin lesions typical for Borrelia bacteria by an antibiotic therapy carried out lege artis, patients often complain about a general feeling of weakness and illness with muscle and joint complaints for months. These unspecific symptoms are called "postinfectious syndrome". The term "chronic Lyme disease" is misleading for this clinical picture. There are no indications for a pathogen persistence. An antibiotic therapy is not necessary. Instead, long-term antiphlogistic therapy is necessary.

Repellents: In mild weather, avoid undergrowth and tall grass, wear closed, light-coloured clothing and sturdy footwear. Tuck trouser legs into socks. Rub legs and arms with repellents (effective up to 4 hours). Inspect entire body after exposure.

Early removal of tick: In case of tick bite with tick still present: Remove tick, use thin, firm tweezers, grasp tick as close to biting tools as possible and pull out. The tick's body should not be squeezed or covered with oil or glue to avoid increased secretion of saliva containing the pathogen. The earlier the tick is removed, the less likely it is to transmit the pathogen (from 12 hrs after the bite).

Oral antibiotics: The opinions of the various professional associations differ with regard to prophylactic administration after a tick bite. For example, the current guidelines of the French scientific society reject the initiation of antibiotic therapy. In contrast, the U.S. professional societies of rheumatologists, neurologists, and infectious disease specialists (2020) recommend a single dose of doxycycline after a tick bite. In a meta-analysis with 376 patients, a risk ratio (relative risk=RR) was calculated for the rates of unfavorable events (e.g. Lyme disease or erythema migrans) in patients who received an intervention compared to the respective control group with antibiotic-free standard therapy. In the oral antibiotic group, 0.2% suffered an adverse event (95% CI: 0.0-1.0%), compared with 2.5% in the control group (95% CI: 1.7-3.5%). Pooled relative risk RR: 0.29 (95% CI: 0.15-0.57).No adverse event occurred in the subgroup of patients who received an antibiotic for ten days, compared with 1.3% (95% CI: 0.3-2.9%) in the controls; pooled RR: 0.28 (95% CI: 0.05-1.67). When only patients receiving a single dose of 200mg doxycycline were compared with fecal rolls, the pooled event rate was 0.8% (95% CI: 0.4-1.4%) vs. control at 3.0% (95% CI: 2.0-4.2%). This corresponds to a pooled RR of: 0.29 (95 % CI: 0.14-0.60). Consequence of this analysis is the recommendation of a single dose of 200mg doxycycline p.o. after a tick bite. (Zhou G et al 2021)

Local antibiosis: At the site of the bite, a 10% azithromycin gel applied several times 12-hourly no later than 3 days after the bite can prevent infection. However, in a larger study, significance for clinical efficacy was not producible (Schwameis M et al. 2016).

TBE: Vaccination during a stay (e.g. holiday) in endemic areas.

Stages and clinical manifestations of Lyme borreliosis

• The risk of infection after a tick bite can be estimated more accurately by examining the tick for B. burgdorferi (PCR diagnostics). The prophylactic administration of antibiotics in a given case can prevent diseases and save the health care system considerable costs.
• It is discussed whether an infection with Borrelia burgdorferi plays a pathogenetic role in atrophodermia idiopathica et progressiva. In a study with 17 volunteers 53% IgG antibodies against Borrelia burgdorferi could be detected.
• After infection and adequate antibiotic treatment of Lyme disease, unspecific symptoms such as impaired performance, fatigue and impaired concentration are often reported. This complex of symptoms is described as post-lymphic syndrome. Whether a new antibiotic therapy cycle should then take place is still open at present.
• Infection during pregnancy: In some larger epidemiological studies (35,000 pregnant women; 1500 infants and children) no increased risk of malformations, prematurity, fruit death could be proven.
• Long-term administration of Ceftriaxone is associated with the risk of pseudomembranous colitis caused by Clostridium difficile.
• A Borrelia infection does not leave a permanent immunity. Reinfections are possible!
• In a meta-analytical review (19 studies with 2532 patients), no differences in the efficiency of the individual antibiotics (amoxicillin/ doxycycline; cefurroxime axetil; ceftriaxone; azithromycin, phenoxymethylpenicillin, minocycline) could be found. There were also no significant differences in the side effect profile (Torbahn G et al. 2018).

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